After traumatic brain injury (TBI) the human APOE-?4 (APOE4) gene polymorphism is associated with increased mortality, increased coma time, poor prognosis, and an increased risk of late-onset Alzheimer's disease (AD). The APOE4 gene is found in 27% of the US population, and as such affects an estimated 459,000 TBI cases each year. It is not known how APOE4 genotype negatively impacts outcome after TBI, or if genotype-specific treatments are required to improve prognosis. TBI causes the accumulation and deposition of a neurotoxic peptide called amyloid- (A). Approximately 30% of all fatal TBI cases present with A plaques, however the deposition of A is dependent on the APOE genotype of the patient. Only 10% of non-APOE4 brains have A plaques after injury, while 35% of heterozygous APOE4 brains, and 100% of homozygous APOE4 brains, develop A plaques. The APOE gene encodes for the apolipoprotein E (apoE) protein, which was recently shown to facilitate the enzymatic degradation of A. These data suggest that individuals carrying the APOE4 genotype are unable to clear the excess A that is produced as a result of TBI. Accumulation of excess A is known to cause neuronal apoptosis and trigger neuroinflammation. We have recently shown that preventing A production, or enhancing A clearance, can ameliorate secondary injury and prevent cognitive and motor deficits caused by experimental TBI in mice. Here we will study the role of apoE isoforms in A clearance after TBI. We are testing the hypothesis that apoE is instrumental in A degradation after TBI, but the apoE4 isoform is dysfunctional at this process. We believe that the accumulation of A in APOE4 mice leads to increased cell death and poorer functional and cognitive outcome after injury. We will test this hypothesis in our Specific Aims: Aim 1) Determine the role of apoE in A clearance after TBI Aim 2) Determine the effect of APOE genotype on A clearance after TBI Aim 3) Test if the poorer prognosis after TBI in APOE4 carriers is due to prolonged A accumulation These data will allow us to determine the mechanism by which A accumulates aggressively in APOE4 patients after TBI, and the functional consequences of that A accumulation.